Enhanced safety surveillance of GSK's quadrivalent seasonal influenza vaccine in Germany and Spain (2021/2022 season) using an electronic patient‐reported outcome system for vaccine safety remote monitoring

Abstract Background Seasonal influenza epidemics are managed through vaccination each winter in the European Union, to prevent infections, complications, and deaths. As circulating virus strains vary unpredictably, vaccines are reformulated annually, and their safety monitored rapidly and continuously at the start of each season, following European Medicines Agency guidelines.Seasonal influenza epidemics are managed through vaccination each winter in the European Union, to prevent infections, complications, and deaths. As circulating virus strains vary unpredictably, vaccines are reformulated annually, and their safety monitored rapidly and continuously at the start of each season, following European Medicines Agency guidelines. Methods This enhanced safety surveillance study assessed pre‐specified and other adverse events (AEs) occurring within 7 days of GSK's inactivated quadrivalent seasonal influenza vaccine (IIV4) in children and adults in Spain and Germany. As the study was conducted during the COVID‐19 pandemic (2021/2022 season), data were collected electronically, using a web portal or call center. Results Safety was assessed in 737 participants (median age 49 and 9 years in Germany and Spain, respectively, 19.3% with a chronic medical condition). After Dose 1 and Dose 2, respectively, 332 (45.1%) and 5 (26.3%) participants reported at least one AE, primarily pre‐specified AEs. The most common AEs after Dose 1 (adults and children) were injection site pain, swelling or erythema, headache, and fatigue. After Dose 2 (in children), the most common AEs were injection site pain, rhinorrhea, fatigue, and decreased appetite. No new or unexpected safety issues were identified. Conclusion This study supports and confirms the safety profile of GSK's IIV4 in all age groups with a vaccine indication. The new electronic safety reporting method (with response rates of 75.4% following Dose 1 and 100% following Dose 2) provides an alternative for future studies to reduce the burden on sites or in case site visits are not feasible.


| INTRODUCTION
In Europe, seasonal influenza epidemics occur each winter, typically between November and April, and affect all age groups. Uncomplicated cases can experience fever, headache, muscle pain, sore throat, and cough, lasting days to weeks. Severe cases or secondary bacterial infections can lead to pneumonia, encephalitis, or myocarditis and can be fatal, especially in vulnerable populations, for example, chronic conditions, older adults, and infants. 1 Influenza remains a major public health burden [1][2][3] ; however, annual vaccination plays a pivotal role in reducing the risk of infection and complications. 4 Influenza types A and B viruses, and their respective A subtypes and B lineages, cause most disease, and circulating strains vary unpredictably each winter. 5 Due to frequent genetic and antigenic changes in influenza viruses, 6 seasonal vaccines are reformulated with updated viral strains and therefore need constant benefit-risk monitoring.
To comply with European Medicines Agency requirements, 7,8 following close dialog with regulators of the European Union, 9 GSK launched a series of enhanced safety surveillance (ESS) studies from the 2015/2016 season onwards. [10][11][12][13] The present ESS study of GSK's inactivated quadrivalent seasonal influenza vaccine (IIV4) was implemented in Germany and Spain to monitor the frequency and severity of adverse events (AEs) experienced within 7 days following vaccination in near real time. This year, in anticipation of potential COVID-19 challenges to the study, data were collected using an electronic Case Report Form (e-CRF) completed by investigators and participants via an electronic Patient Reported Outcome (e-PRO) web-based portal or with help from a call center.
The primary objective was to estimate the cumulative percentage of participants reporting pre-specified adverse events of interest (AEIs) and any other AEs occurring within 7 days of vaccination with GSK's IIV4 in each country and overall. As this study was conducted during the COVID-19 pandemic, potential logistical, site access, and medical staff constraints were anticipated. This study was thus also intended to provide information about potential effects of the pandemic on the reporting of influenza vaccine safety. Figure 1 presents a graphical plain language summary.

| Study design and population
This prospective ESS study of GSK's IIV4 (Influsplit Tetra in Germany, Fluarix Tetra in Spain -GSK study ID 213828) was conducted between October 1, 2021 and January 7, 2022. ESS studies aim to identify potential safety signals early on, and the use of electronic reporting in this study may help to inform future safety surveillance studies for influenza in Europe. Pre-specified AEIs were considered as well as open fields to report any non-listed AEs or the absence of any AEs.
Participants, or legal representatives, provided written informed consent prior to enrolment and were vaccinated with GSK's IIV4 according to routine country-specific practices and local guidelines. 14 A second dose of GSK's IIV4 was administered only to children aged <9 years who have not previously been vaccinated against influenza.
Participants completed the adverse drug reaction (ADR) questionnaire (for type and severity of AEs) and a COVID-19 assessment form (for history of COVID-19 infections as well as associated signs and symptoms) using a web-based e-PRO portal or with help from a call center.
Healthcare professionals (HCPs) were to report any serious AE (SAE) that they deemed related to GSK's IIV4 within 24 h of becoming aware of it, using the electronic reporting system.
The goal was to enroll approximately 1000 participants from five HCPs across Germany and Spain (from October 1 up to December 31, 2021) and to include participants in all age groups for which IIV4 is indicated, that is, from 6 months of age. Recruitment targeted participants aged over 6 months in Spain and adults aged 18 years and older in Germany. Children in care were not eligible for this study.

| Statistical methods
All analyses were descriptive. The analysis of AEs was performed on the Safety Set, which included all enrolled vaccinated participants who initiated activities to receive the login details for the web portal, or contact details for the call center, to complete the ADR.
Demographic characteristics and risk status for influenzaassociated morbidity and mortality were summarized using frequency tables (n, %) for categorical variables and mean, standard deviation, median, minimum, and maximum for continuous data.
The number and percentage of participants who received coadministered vaccination on the same day as the GSK's IIV4 were tabulated by vaccination class. The percentage of participants who completed the ADR card and COVID-19 form was tabulated by center/ country.
For each vaccine dose, the cumulative percentage of participants reporting AEs within 7 days of vaccination was estimated each week from study start (i.e., using International Standards Organization [ISO] weeks 39 to 52) and using the Medical Dictionary for Regulatory Activities (MedDRA 15 ), Primary System Organ Class (SOC), and Preferred Term (PT). In addition, for each vaccine dose, the weekly and cumulative percentages of participants reporting AEs were estimated by age strata (6 months to 17 years; 18 to 65 years; >65 years) and risk status (at risk/not at risk) for each country. These secondary objectives are not presented here but will be available in the GSK clinical trial register (GSK Study ID 213828) 16 by March 2023.
The cumulative percentages of participants reporting AEs by severity grade were also calculated over the whole study period.
The 95% confidence intervals (CIs) accounting for the clustering effect of centers were computed on all estimated percentages (extended Clopper-Pearson exact CI for clustered data). The design effects and the intracluster correlation coefficients were also estimated for the cumulative percentage of participants reporting AEs by MedDRA Primary SOC and PT within 7 days post-each vaccination using the completed ADR questionnaire, over the whole study period. Overall, 268 participants were lost to follow-up, and three withdrew F I G U R E 1 Graphical plain language summary. consent but not due to an AE ( Figure 2). In total, 706 (72.3%) participants completed the study (i.e., completed the ADR in Spain (Table S1).
The most frequently reported AEs, by at least 5% of participants, following Dose 1 were (by MedDRA PT) as follows: injection site pain (31.8%), fatigue (11.4%), headache (9.8%), injection site swelling (8.7%), and injection site erythema (5%) ( General disorders and administration site conditions were the most commonly reported MedDRA SOCs (i.e., three participants with injection site pain and two with fatigue), followed by respiratory, thoracic, and mediastinal disorders (i.e., three participants with rhinorrhea); metabolism and nutrition disorders (i.e., two participants with decreased appetite); and psychiatric disorders (i.e., one participant with irritability) ( Table 3). Assessed by the HCP based on medical judgment and experience. b Participants may be assigned to more than one risk group; Five participants reported "Other" Geographic ancestry in Spain (Other = "Hispanic or Latino").  Figure 3A shows the number of participants enrolled in each country, by dose, each week. Participants in Germany were adults and therefore received one dose of GSK's inactivated quadrivalent influenza vaccine, while some participants in Spain were children eligible for two doses. Figure 3B shows the cumulative number of enrolled participants by week and country, showing in darker shades the number reporting at least one AE within 7 days of Dose 1 or Dose 2.
T A B L E 2 Cumulative participants (%) reporting AEIs (in green) and/or other AEs post-Dose 1 over study period (Safety Set).   Note: In green are pre-specified AEIs. AEs that occurred in three or fewer cases were grouped to simplify the of AEs were of similar or lower magnitude than those in the SmPC. 18 The electronic ADR (using the e-PRO web-based platform or call center) was completed by 75.4% of participants following Dose 1 and 100% following Dose 2, which was lower than previous IIV4 ESS studies using paper cards. 13,19 Some participants/site staff found the electronic platform difficult to use, despite supportive documentation and training. Per protocol, the call center option could not be used by minors, even with parental supervision, which may have posed logistical issues for some sites/participants. Although the electronic ADR completion rate was lower than traditional active studies, 20 or webbased intensive monitoring, 21 the completion rate in this study falls within the range observed in other surveillance studies using an e-PRO system. [22][23][24] Therefore, e-PRO systems can still be used to collect safety information, for example, to limit the burden of work for sites or to monitor safety when a site visit is not possible, for example, during COVID-19 lockdowns.
Systematic collection of medical history associated with COVID-19 infections and symptoms allowed us to better appreciate and empirically observe any potential interference with the vaccination process and IIV4 safety profile. Ultimately, findings were aligned with previous seasons and did not differ from the last season which also occurred during the COVID-19 pandemic. Co-administration of any other vaccines on the same day as GSK's IIV4 was also captured; however, due to the relatively limited numbers reported (i.e., 11.2% for Dose 1 and none for Dose 2), it was challenging to observe or evaluate trends or impact on frequency of AEs experienced.
The study bears some limitations. As Belgian sites declined to participate this year, recruitment targets in Germany and Spain were increased to reach the required sample size. Spanish sites were able to enroll participants on a two-dose vaccination schedule (i.e., children <9 years old not previously vaccinated against influenza), to cover all ages indicated for GSK's IIV4. Limitations in the e-PRO system and associated e-CRF meant it was not possible to directly identify participants who had received the login details or call center contact details as planned. Therefore, as a proxy at the analysis stage, these participants were identified if they initiated the first activities to complete the ADR questionnaire (i.e., either opening the web-based ADR questionnaire or contacting the call center). The e-PRO system did not allow data related to AEs entered in the system to be queried (e.g., date typos). Despite these limitations, ESS studies contribute to T A B L E 3 Cumulative participants (%) reporting AEIs (in green) and/or other AEs post-Dose 2 over study period (Safety Set).  Note: In green are pre-specified AEIs. Abbreviations: 95% CI, 95% confidence interval (extended Clopper-Pearson exact CI for cluster data); AE, adverse event; AEI, adverse event of interest; LL, lower limit; MedDRA, Medical Dictionary for Regulatory Activities; N, total number of participants; n (%), number (percentage) of participants reporting the symptom at least once; UL, upper limit.
T A B L E 4 Cumulative participants (%) reporting AEIs (in green) and/or other AEs post-doses 1 and 2 over study period-Spain (Safety Set).  Note: In green are pre-specified AEIs. Abbreviations: 95% CI = 95% confidence interval (extended Clopper-Pearson exact CI for cluster data); AE, adverse event; AEI, adverse event of interest; LL, lower limit; MedDRA, Medical Dictionary for Regulatory Activities; N, total number of participants; n a , number of specified AEs reported; n (%), number (percentage) of participants reporting the AE at least once; UL, upper limit.

DATA AVAILABILITY STATEMENT
Anonymized individual participant data and study documents can be requested for further research (www.clinicalstudydatarequest.com).

ETHICS STATEMENT
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
The following IECs or IRBs and Regional Authorities were con-

PATIENT CONSENT STATEMENT
Informed consent was obtained from all individual participants included in the study.

TRADEMARKS
Influsplit Tetra and Fluarix Tetra are trademarks owned by or licensed to GSK.